Sandra M. Donnelly

Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

BACKGROUND Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin system. METHODS We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. RESULTS A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo. CONCLUSIONS Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.)

Risk Factors for the Development of Cephalic Arch Stenosis

Purpose The creation of a vascular access is necessary in hemodialysis patients, including those with marginal vessels. Upper arm fistulae are attractive due to the ease of creation and of achieving high access flow rates. Cephalic arch stenosis (CAS) can lead to failure of upper arm fistulae and is increasingly identified. We hypothesized that CAS is promoted by high blood flow rates, brachiocephalic fistulae, and an angle of cephalic vein insertion approaching 90 degrees. Methods All patients requiring a fistulogram between January 2004 and May 2006 had surveillance fluoroscopy of the central veins. Demographic, clinical and laboratory parameters were collected and the angle of the cephalic vein insertion measured by 3 blinded independent observers. Results Fifty-eight patients had fistulograms and CAS was detected in 18 subjects. Significant differences between the CAS and non-CAS groups were brachiocephalic fistula site (p=0.046), access flow (mL/min) (p=0.012), and absence of diabetes (p=0.03). Univariate predictors of CAS include access flow (per 100 mL/min) (p=0.042), platelet count (p=0.031) and calcium-phosphate product (p=0.026). The relationship of brachiocephalic site and CAS was confounded by access flow [(per 100 mL/min)*brachiocephalic fistula site (p=0.016)] and fistula age [brachiocephalic fistula site*fistula age (p=0.017)]. In multivariate analysis, renovascular disease, calcium-phosphate product, platelet count and access flow (per 100 mL/min)*brachiocephalic fistula predicted CAS (p<0.001, Negelkerkes R-Square= 0.55). The angle of insertion of the cephalic vein was not predictive for CAS. Conclusions CAS may be a long-term consequence of high blood flow rates. The interaction of access flow and brachiocephalic fistula supports the hypothesis that high flow through a brachiocephalic fistula promotes CAS. The multiple factors influencing cephalic arch remodeling require further research.

A simple method to create buttonhole cannulation tracks in a busy hemodialysis unit

The preference for fistulae as the hemodialysis access of choice has led to a significant number of accesses that are less than ideal for cannulation. Buttonhole cannulation is ideal for such accesses, but the technique for creation provides major challenges. In 12 patients, buttonhole tunnel tracks were created by leaving the polyurethane catheter of a Clampcath® hemodialysis needle indwelling for 10 days after the initial cannulation. After each dialysis the catheter was flushed, and dressed with an antibacterial ointment and gauze. Dialysis was carried out via the catheter during that time. After day 10, the catheter was removed, the tunnel track covered with an antibacterial dressing and the tunnel track was cannulated with a dull buttonhole needle at the next dialysis. Successful buttonhole accesses were created in 11 patients after 10 days, the 12th patient required a single sharp needle cannulation before using dull needles. During the first 2 weeks of dull needle cannulation both pain experienced on cannulation and the difficulty cannulating the access were significantly less than in the classical buttonhole technique (P<0.01). Complications during the follow‐up period (6 months–1.5 years) included difficulty cannulating with a dull needle (22) and antibacterial agent induced contact dermatitis (4). There was no episode of sepsis or tunnel track infection. Initial cannulation of the fistula using a Clampcath® hemodialysis needle, leaving the polyurethane catheter indwelling for 10 days, is a simple, safe, and effective technique for the creation of buttonhole tunnel tracks.

The relationship of retinal vessel diameter to changes in diabetic nephropathy structural variables in patients with type 1 diabetes.

Aims/hypothesisWe examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy.MethodsPersons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up (n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index.ResultsWhile controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [Vv(Int/cortex)] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints.Conclusions/interpretationIndependently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv(Int/cortex), a measure of interstitial expansion in persons with type 1 diabetes mellitus.

Relationship of Blood Pressure to Retinal Vessel Diameter in Type 1 Diabetes Mellitus

OBJECTIVE To examine the relationship of blood pressure (BP) and use of angiotensin-receptor blocker or angiotensin-converting enzyme inhibitor to retinal vessel diameter in normotensive, normoalbuminuric persons with type 1 diabetes mellitus. METHODS In a randomized, controlled clinical trial, clinic and 24-hour ambulatory BPs were measured in persons with type 1 diabetes mellitus and gradable fundus photographs both at baseline (n = 147) and at 5-year follow-up (n = 124). Retinal arteriole and venule diameters were measured by a computer-assisted technique. Individual arteriole and venule measurements were combined into summary indexes that reflect the average retinal arteriole (central retinal arteriole equivalent [CRAE]) and venule (central retinal venule equivalent [CRVE]) diameter of an eye, respectively. RESULTS While controlling for age, study site, glycosylated hemoglobin level, and ambulatory pulse rate, the daytime ambulatory systolic (-0.29-microm effect per 1 mm Hg; P = .02), daytime ambulatory diastolic (-0.44-microm effect per 1 mm Hg; P = .04), nighttime ambulatory systolic (-0.27-microm effect per 1 mm Hg; P = .03), and 24-hour ambulatory systolic (-0.31-microm effect per 1 mm Hg; P = .03) BPs were cross-sectionally associated with a smaller CRAE. While controlling for age, study site, glycosylated hemoglobin level, ambulatory pulse rate, and baseline CRAE, no BP measure was associated with a change in CRAE or CRVE during 5 years of follow-up. Treatment with losartan potassium or enalapril maleate was not associated with a statistically significant change in CRAE or CRVE. CONCLUSION Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker therapy does not affect retinal arteriole or venule diameter in normotensive persons with type 1 diabetes mellitus. Trial Registration clinicaltrials.gov Identifier: NCT00143949.

Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus

BACKGROUND Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal inflammation. We examined their association with development of diabetic nephropathy (DN) lesions in normotensive normoalbuminuric subjects with type 1 diabetes (T1D) from the Renin-Angiotensin System Study. METHODS Biomarker concentrations were measured in baseline urine samples from 224 subjects who underwent kidney biopsies at baseline and after 5 years. Fifty-eight urine samples below the limit of quantitation (LOQ, 28.8 pg/mL) of the MCP-1 assay were assigned concentrations of LOQ/√2 for analysis. Relationships between ln(MCP-1/Cr) or ln(hepcidin/Cr) and morphometric variables were assessed by sex using multiple linear regression after adjustment for age, T1D duration, HbA1c, mean arterial pressure, albumin excretion rate (AER) and glomerular filtration rate (GFR). In models that examined changes in morphometric variables, the baseline morphometric value was also included. RESULTS Baseline mean age was 24.6 years, mean duration of T1D 11.2 years, median AER 6.4 µg/min and mean iohexol GFR 129 mL/min/1.73 m(2). No associations were found between hepcidin/Cr and morphometric variables. Higher MCP-1/Cr was associated with higher interstitial fractional volume at baseline and after 5 years in women (baseline partial r = 0.244, P = 0.024; 5-year partial r = 0.299, P = 0.005), but not in men (baseline partial r = -0.049, P = 0.678; 5-year partial r = 0.026, P = 0.830). MCP-1 was not associated with glomerular lesions in either sex. CONCLUSIONS Elevated urinary MCP-1 concentration measured before clinical findings of DN in women with T1D was associated with changes in kidney interstitial volume, suggesting that inflammatory processes may be involved in the pathogenesis of early interstitial changes in DN.

When Is a New Fistula Mature? The Emerging Science of Fistula Cannulation

Once an arteriovenous fistula is established, the blood vessels are subjected to marked changes in hemodynamic forces that trigger remodeling to re-establish baseline parameters of sheer and hoop stress. These homeostatic processes culminate in two requirements that define an adequate and enduring access. First, blood flow must increase to provide amounts that will provide adequate delivery of blood to the artificial kidney. Second, the vessel wall must undergo changes that will allow it to withstand repeated cannulation. Hence, a fistula is mature when it can do what it sets out to do (flow readiness) despite what is being done to it (cannulation readiness). Although flow has been measured with Doppler, high-frequency ultrasound is needed to measure vessel wall thickness to determine hoop stress. Beyond the wall of the vessel, the concept of cannulation readiness depends on the skill and expertise of the cannulator.

Glutathione and riboflavin status in supplemented patients undergoing home nocturnal hemodialysis versus standard hemodialysis.

BACKGROUND Patients on conventional hemodialysis (HD) have elevated markers of oxidative stress and chronic inflammation, which may contribute to a high prevalence of cardiovascular disease. Glutathione (GSH), an important intracellular antioxidant, requires cysteine as a rate-limiting amino acid for its synthesis and riboflavin for its regeneration. OBJECTIVES We aimed to examine whether erythrocyte GSH (eGSH) concentrations and riboflavin status are influenced by the increased dialysis dose provided to vitamin-supplemented patients receiving home nocturnal hemodialysis (HNHD) (6-8 hours/session, 5-7 nights/week) compared with patients on standard hemodialysis (SHD) (4 hours/session, 3 days/week). METHOD This was a cross-sectional comparative study involving 30 patients undergoing SHD or HNHD regimens and a group of 15 healthy control subjects (HC). We measured eGSH concentration by liquid chromatography-tandem mass spectrometry, riboflavin status by eGSH reductase activity coefficient (EGRAC) as well as plasma total cysteine (Cys) and total homocysteine (Hcy), vitamin C by high-performance liquid chromatography, and C-reactive protein (CRP) by standard method. Estimated dietary protein and energy intakes were determined by 3-day food records, and nutritional status was assessed by subjective global assessment (SGA). RESULTS There were no significant differences among groups in eGSH concentration, EGRAC, dietary protein intake, and SGA score. SHD patients had significantly higher plasma Cys (P < .001) and Hcy compared with HNHD and HC groups (P = .048). Vitamin C was significantly lower (P = .01) and CRP significantly higher (P = .048) in both HD groups compared with HC. CONCLUSION eGSH concentration appears to be unaffected by dialysis dose in well-nourished HD patients.

Supercath Safety Clampcath buttonhole creation: complication of catheter breakage.

The creation of buttonhole tracks with Supercath Safety Clampcath is a novel and simple technique that allows dull fistula needle insertions with relative ease and diminished pain. As greater experience with this procedure develops, new issues arise for consideration. We report an unexpected complication of Supercath Safety Clampcath catheter breakage that may be due to physical distortions as a result of its location in the antecubital fossa just proximal to the elbow joint. We present a review of our experience and a framework for the safe ongoing use of this device for creation of buttonholes in fistula for hemodialysis.

Comparing the automated versus manual method of needle biopsy for renal histology artefacts

Percutaneous renal biopsy was first introduced in 1934, and the Vim-Silverman needle modified by Franklin was introduced in 1954 [1]. More recently, renal biopsies have been performed using the spring-loaded biopsy gun [2]. While renal biopsy needles have been evaluated for tissue adequacy and patient safety, their effect on the quality of the tissue has not been previously described. This study compared the quality of the renal tissue obtained for electron microscopy (EM) between two renal biopsy needles, the 14-gauge (G) Vim-Silverman needle and the 16G automated BioptyTM gun using tissues obtained during the conduct of a clinical trial.